<p>Bone tissue engineering (BTE) has emerged as a promising alternative to traditional bone grafting methods with limitations such as donor scarcity and immunogenic complications. This study evaluated the efficacy of a Sodium Alginate/Gelatin/Hydroxyapatite scaffold enhanced with <i>Hesperetin</i>, a bioactive flavonoid, in bone regeneration. The scaffold was fabricated using the freeze-drying technique and was characterized through various physicochemical and biological evaluations to assess its suitability for tibial regeneration. In in-silico studies were incorporated to identify <i>Hesperetin’s</i> potential targets of hesperetin in bone application, revealing its interaction with key osteogenic and anti-inflammatory pathways. The results indicated that the treated scaffolds exhibited improved characteristics compared with the control group. The surface morphology of the scaffolds confirmed that the porous microstructure was advantageous for cell adhesion, whereas the MTT results revealed enhanced osteoblast viability. These findings highlight the potential of flavonoid-enhanced scaffolds in regenerative medicine, offering a biocompatible and efficacious solution to bone defects.</p> Graphical abstract <p></p>